RAF kinase modulator compounds and methods of use thereof

Abstract

Compounds, compositions and methods are provided for modulating the activity of RAF kinases, including BRAF kinase and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by RAF kinases.

What is claimed is: 
     
       1. A compound having formula XVII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein X is O or S; 
         R 1a  and R 1b  are selected as follows: 
         i) R 1a  and R 1b  are each independently alkoxy, alkoxyalkoxy, alkylsulfonylalkoxy or a group of formula: 
       
       
         
           
           
               
               
           
         
         where K is a direct bond or alkylene, optionally substituted with a hydroxy group; 
         A is N or CH; 
         Y is —O, —S(O) 2 , —N(R 14 ) or —C(H)R 15 ; 
         p is 0 or 1; 
         R 14  is hydrogen, alkyl, haloalkyl, hydroxyalkyl or S(O) t R 13 ; 
         R 15  is hydrogen, halo, alkyl, hydroxyalkyl or —OR 12 ; 
         t is 1 or 2; 
         R 12  is hydrogen or alkyl; and 
         R 13  is alkyl; or 
         ii) R 1a  and R 1b  groups together form an alkylenedioxy group; and 
         R 10  is hydrogen, halo, alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl or cycloalkylalkyl; where alkyl, aryl, heterocyclyl and heteroaryl groups are optionally substituted with 1-3 groups selected from halo, cyano, hydroxyl and alkoxy. 
       
     
     
       2. The compound of  claim 1  having formula XIX: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein X is O or S;
 R 1a  and R 1b  are selected as follows: 
 i) R 1a  and R 1b  are each independently methoxy, methoxyethoxy, methylsulfonylpropyloxy, or a group of formula: 
 
       
       
         
           
           
               
               
           
         
         
           where K is ethylene or propylene, optionally substituted with a hydroxy group; 
           A is N or CH; 
           Y is —O, —S(O) 2 , —N(R 14 ) or —C(H)R 15 ; 
           p is 1; 
           R 14  is hydrogen, methyl, hydroxyethyl, or methylsulfonyl; 
           R 15  is hydrogen, hydroxymethyl, hydroxyethyl or hydroxy; or 
           ii) R 1a  and R 1b  groups together with the carbon atoms on which they are substituted form an ethylenedioxy group; and 
           R 10  is hydrogen, halo, alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl or cycloalkylalkyl; where alkyl, aryl, heterocyclyl and heteroaryl groups are optionally substituted with 1-3 groups selected from halo, cyano, hydroxyl and alkoxy. 
         
       
     
     
       3. A compound of  claim 1  that is 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea or a pharmaceutically acceptable salt thereof. 
     
     
       4. A compound that is 
       
         
           
           
               
               
           
         
       
     
     
       5. A pharmaceutically acceptable salt of the compound 
       
         
           
           
               
               
           
         
       
     
     
       6. A composition comprising 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
       7. A method of treating a cancer associated with activated BRAF kinase comprising administering to a patient in need thereof 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method of  claim 7 , wherein the cancer is melanoma. 
     
     
       9. The method of  claim 7 , wherein the cancer is thyroid cancer. 
     
     
       10. The method of  claim 7 , wherein the cancer is colorectal cancer. 
     
     
       11. The method of  claim 7 , wherein the cancer is non-small cell lung cancer. 
     
     
       12. A method of inhibiting the activity of a mutated form of BRAF kinase by administering 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea or a pharmaceutically acceptable salt thereof. 
     
     
       13. The method of  claim 12 , wherein the mutated form is a V600 mutant. 
     
     
       14. The method of  claim 13 , wherein the V600 mutant is V600E.